Scientific rationale

Vicore is unlocking the potential of a new class of drugs – Angiotensin II Type 2 Receptor Agonists (ATRAGs) – stopping disease progression and restoring function.

The Renin-Angiotensin System (RAS)

ACE: Angiotensin Converting Enzyme. ARB: Angiotensin Receptor Blocker. ATRAG: Angiotensin II Type 2 Receptor Agonist. AT1R: Angiotensin II Type 1 Receptor. AT2R: Angiotensin II Type 2 Receptor.

The Renin-Angiotensin System (RAS) is an evolutionarily well conserved system, crucial for body and tissue homeostasis. The discovery of renin in the late nineteenth century and angiotensin in the 1930’s has given rise to new drug classes, the angiotensin type 1 receptor blockers (ARBs) and the angiotensin converting enzyme (ACE) inhibitors which together have revolutionized the treatment of hypertension.

The protective arm of the RAS is triggered through activation of the AT2 receptor and has been largely unexploited until the synthesis of buloxibutid (C21) – a first-in-class, orally available, low molecular weight AT2 receptor agonist.

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Multimodal action of AT2 receptor activation with broad therapeutic potential

Green arrows and boxes indicate key AT2 receptor signaling pathways. Green bold arrows indicate effects of AT2 receptor stimulation. PP2A (serine-threonine protein phosphatase-2A), MKP-1 (MAPK phosphatase 1), SHP-1 (Src homology region 2 domain-containing phosphatase-1), Akt (protein kinase B), PPAR? (peroxisome proliferator-activated receptor- ?), EMT ( Epithelial mesenchymal transition), ECM (extracellular matrix)

It is well documented that AT2 receptor activation can stop disease progression and promote tissue regeneration and organ function in experimental models of pulmonary, cardiovascular, renal, metabolic and CNS disease.  Such therapeutic effects mediated by the AT2 receptor pathway involve improved endothelial function and down-regulation of inflammatory, fibrotic and senescence processes.

The protective function of the AT2 receptor is also in line with the receptor being upregulated in injured tissues.  Importantly, the AT2 receptor pathway is not only a mechanism that counteracts the negative effects of AT1 receptor activation but is rather an endogenous mechanism for resolution and repair in general.